Membrane proteins comprise around 20-30% of a typical proteome and play crucial roles in a wide variety of biochemical pathways. Apart from their general biological significance, membrane proteins are of particular interest to the pharmaceutical industry, being targets for more than half of all available drugs. This thesis focuses on prediction methods for membrane proteins that ultimately rely on their amino acid sequence only. By identifying soluble protein domains in membrane protein sequences, we were able to constrain and improve prediction of membrane protein topology, i.e. what parts of the sequence span the membrane and what parts are located on the cytoplasmic and extra-cytoplasmic sides. Using predicted topology as input to a profile-profile based alignment protocol, we managed to increase sensitivity to detect distant membrane protein homologs. Finally, experimental measurements of the level of membrane integration of systematically designed transmembrane helices in vitro were used to derive a scale of position-specific contributions to helix insertion efficiency for all 20 naturally occurring amino acids. Notably, position within the helix was found to be an important factor for the contribution to helix insertion efficiency for polar and charged amino acids, reflecting the highly anisotropic environment of the membrane. Using the scale to predict natural transmembrane helices in protein sequences revealed that, whereas helices in single-spanning proteins are typically hydrophobic enough to insert by themselves, a large part of the helices in multi-spanning proteins seem to require stabilizing helix-helix interactions for proper membrane integration. Implementing the scale to predict full transmembrane topologies yielded results comparable to the best statistics-based topology prediction methods.

La riforma attuata nel ramo femminile dell'ordine di San Benedetto da Catherine Mectilde de Bar [Madre Mectilde del Santissimo Sacramento] (1614-1698). La formazione, l'opera e gli incontri della religiosa lorenese sullo sfondo delle vicende politiche ed ecclesiali della Francia del XVII secolo. Gli aspetti storici, istituzionali e teologici legati alla fondazione e allo sviluppo dell'Istituto delle benedettine dell'Adorazione Perpetua del Santissimo Sacramento. / The reform realised by Catherine Mectilde de Bar [Mother Mectilde of the Most Holy Sacrament] (1614-1698) in the feminine branch of the Benedictine Order. The formation, the works and the writings of this nun from Lorraine in the midst of the political and ecclesial events in seventeenth century France. The historical, institutional and theological aspects connected with the foundation and the development of the institute of the Benedictine nuns of the perpetual adoration of the Most Holy Sacrament.

Les instabilités générées par frottement sont responsables des divers bruits tels que le crissement, le sifflement ou le broutement ... Pour modéliser et comprendre ce phénomène d'instabilités, les analyses temporelle et fréquentielle sont utilisées sur un système modèle constitué de deux poutres en contact. Dans l'analyse fréquentielle, linéaire, l'instabilité se manifeste par la coalescence de deux modes propres du système. Dans l'analyse temporelle, qui tient compte de l'aspect non linéaire d'un contact frottant, l'instabilité est caractérisée par des zones d'adhérence ou de décollement qui apparaissent au niveau de la surface de contact. Les résultats issus des deux analyses sont cohérents et complémentaires, malgré quelques différences de prédiction. Une validation expérimentale a été effectuée et montre une bonne corrélation entre les résultats numériques temporels et expérimentaux. On met en évidence la pertinence de l'analyse temporelle dans l'étude des instabilités de contact, phénomène vibratoire complexe. On montre également que, même si elle n'apparaît pas suffisante pour caractériser le phénomène d'instabilité de contact, l'analyse fréquentielle donne de bons résultats. L'aspect tribologique est également abordé et met en évidence une interaction permanente entre les phénomènes aux échelles micro- et macroscopique.

SecA is an essential component for the translocation of proteins across bacterial membranes. Though SecA is known to function in the membrane the mechanism for this process remains unclear. In this study we identify two specific regions of SecA that may be important for N-terminal membrane interactions. Molecular modeling of SecA from the E. coli and B. subtilus crystal structures, previously determined, revealed that the first 30 amino acids of SecA consists of a helix of amino acids 1-11 connected by a linker (amino acids 12-16) to an amphipathic helix of amino acids 17-30. The first helix is dispensable for SecA activity; however, deletions in the second N-terminal helix, at amino acids 21-25, result in decrease of SecA activity and a deletion of 26 amino acids no longer complements E. coli ts mutant BL21.19. We show that the deletions of N-terminal amino acids that result in the decrease of SecA activity are correlated to the loss of SecA membrane binding and integration in these deletion mutants. In this study we also test the accuracy of a new membrane protein prediction software PSSM_SVM. This program predicted an embedded membrane (EM) region at SecA amino acids 110-118. The predicted sequence represents an unusual prediction for an EM region as most membrane integral regions consist of 15-30 amino acids. Molecular modeling indicated that the region 110-118 is a part of a helix composed of amino acids 107-121 in E. coli SecA, and is indicative of a membrane embedded domain. Site-directed mutagenesis was carried out with several conserved residues, which included L110, L114, and L118 to determine if substitutions at these positions would affect SecA activity. Our data shows that most SecA mutants (including some predicted to be inactive) are active in vivo; however, L110E and L114R mutations rendered the mutated SecA non-functional. All together this study shows that the N-terminal limit of SecA resides at amino acid 26 and that amino acids 21-25 may form a N-terminal membrane binding determinate. Moreover, the predicted EM region may indeed correspond to a functional embedded membrane region for SecA.

Protein translocation is essential for bacterial survival and the most important translocation mechanism in bacteria is the secretion (Sec) pathway. Thus targeting Sec pathway is a promising strategy for developing novel antibacterial therapeutics. We report the design, syntheses, mechanistic studies and structure-activity relationship studies using HQSAR and 3-D QSAR Topomer CoMFA analyses of 4-oxo-5-cyano thiouracil derivatives. In summary, introduction of polar group such as –N3 and linker groups such as –CH2-O- enhanced the potency as well as logP and logS several fold. We also report the discovery, optimization and structure-activity relationship study of 1,2,4-triazole containing pyrimidines as novel, highly potent antimicrobial agents. A number of inhibitors have been found to inhibit microbial growth at high nanomolar concentrations.

A combined solution of the Feed-Forward Equalizer (FFE) and Near-End Crosstalk (NEXT) noise cancellation technique was suggested. The techniques increase data throughput and improve link quality in the 20-in FR4 legacy backplane application. Backplane channel loss and coupling noise were measured and characterized to develop the corresponding behavioral channel model. The receiver-side FFE with 4-tap Finite Impulse Response (FIR) filter structure was adopted as the optimum equalizer topology. The 4-tap FIR filter consists of tap delay line with tap-spacing 33 ps and linear tap-gain amplifiers. The tap coefficients were calculated with the Minimum-Mean-Squared-Error (MMSE) algorithm. A 0.18-um CMOS 4-tap FIR filter IC was designed and fabricated. The experiment results showed the 20-Gbit/sec 4-PAM and 10-Gbit/sec NRZ signal were successfully equalized for the 20-in FR4 legacy backplane channel. Moreover, the suggested NEXT noise cancellation technique consists of coarse- and fine-cancellation stages. The 0.18-um CMOS building block ICs such as 7-tap FIR filter, tunable active Pole-Zero (PZ) filter, and a temporal alignment delay line were fabricated. The experiment results showed that 6-dB Signal-to-Noise Ratio (SNR) improvement was achieved by the developed NEXT noise cancellation technique.

The objective of the proposed research is to realize a 10-Gb/sec serial data link over band-limited channels, such as backplanes, multi-mode fiber, and copper-based cables that were originally designed for data rates less than 1Gb/sec. This is achieved using electrical equalization implemented in an integrated circuit (IC). To successfully compensate for various band-limited channels at the targeted data rate with a single equalizer IC, a reconfigurable equalizer topology is proposed. In order to realize the proposed goal, various channels are characterized of their forward transmission frequency response. Based on the measured channel data, system simulations are performed to identify the required specifications for IC implementation. This provides information such as optimal number of taps, fractionally-spaced tap delay, and tap coefficients for the proposed IC. With the obtained system requirements, IC building blocks are designed and fabricated in a 0.18- and #956;m CMOS technology. The fully-integrated reconfigurable CMOS equalizer provides a single-chip solution for compensating various band-limited channels. This enables 10-Gb/sec serial data transmission achieving signal integrity beyond their designed specifications.

This dissertation develops an unclocked receiver analog decision-feedback equalizer (ADFE) circuit architecture and topology and implements the circuit in 0.18-um CMOS to enable 10-Gb/sec serial baseband data transmission over FR-4 backplane and optical fibre. The ADFE overcomes the first feedback-loop latency challenge of traditional digital and mixed-signal DFEs by separating data re-timing from equalization and also eliminates the need for clock-recovery prior to decision-feedback equalization. The ADFE enables 10-Gb/sec decision-feedback equalization using a 0.18-um CMOS process, the first to do so to the author s knowledge. A tuneable current-mode-logic (CML) feedback-loop is designed to enable first post-cursor cancellation for a range of data-rates and to have external control over loop latency over variations in process, voltage and temperature. CML design techniques are used to minimize current consumption and achieve the required voltage swing for decision-feedback to take place. The all-analog equalizer consumes less power and area than comparable state-of-the art DFEs. The ADFE is used to compensate inter-symbol interference (ISI) for 20 inches of FR-4 backplane and 300 m of multi-mode fibre at 10-Gb/sec. The ADFE also extends the reach of single-mode fibre at 10-Gb/sec to 120 km. The work described in this dissertation advances the state-of-the-art in equalization solutions for multi-Gb/sec serial data transmission and can find applications in several of the 10-Gb/sec Ethernet standards that have been approved recently. The contributions of this work toward future research are also discussed.

This study examines whether corporate transparency about a restatement influences the Securities and Exchange Commission's (SEC) decision to issue an enforcement action. I consider corporate transparency to be higher when firms initiate an independent investigation into the restatement, display the restatement in a more prominent press release location, and/or report the restatement in a more visible SEC filing (i.e., Form 8-K). My sample of restatement observations spans nine years, 1997-2005, and is taken from the databases compiled by the General Accounting Office. For each restatement observation, I hand-collect information on SEC enforcement actions from the SEC's website and information on corporate transparency from company press releases and SEC filings. In order to determine the influence of corporate transparency, I develop a model predicting which restatement firms will be sanctioned by the SEC that includes measures of restatement severity, restatement characteristics, firm characteristics, and all three measures of corporate transparency. I find that, on average, greater restatement transparency increases the likelihood of an SEC sanction. This result is strongest before the Sarbanes-Oxley Act of 2002 (SOX), where all three proxies for corporate transparency are positive and significant predictors of SEC enforcement actions. After SOX, however, more visible SEC filings decrease the likelihood of an SEC sanction, suggesting that the SEC rewards this type of transparent behavior. In addition, the SEC also rewards corporate transparency by reducing monetary penalties when an enforcement action is issued. These results extend prior research (Bowen et al. 2005; Files et al. 2008; Gordon et al. 2008; Myers et al. 2008) by providing the first evidence on how corporate transparency affects the SEC's decision to issue an enforcement action. The results may be useful to managers of restating firms and academics researching SEC enforcement actions.

Lots of researches and reports analyzed the success of Samsung Electronics (SEC) mostly focusing on Samsung Group. This paper attempts to look into the relationship between SEC and Samsung Group in terms of SEC¡¦s capital management, and intends to find out if Samsung Group brings advantages to SEC. The analysis in this paper is divided into two parts: ¡]1¡^ examining the source and the use of SEC¡¦s capital by comparing with AUO and PSC¡F¡]2¡^scrutinizing SEC and the Group's financial performances. Firstly, from cash flow's point of view, AUO and PSC depend on substantial financing to meet their capital gap. Differences in working capital also cause impact on cash flow from operating activities. Same results are found similarly in analyzing the SEC and the Group. Moreover, regarding the purpose the capital, SEC evidently shows higher weights in cash outflows from investment activities than in property, plant and equipment. The difference mainly lies in the cross-investments between SEC and Samsung Group. On the other hand, based on the computation of financial ratios, SEC benefits from Samsung Group's integrated supply chains in comparison with AUO and PSC, especially in terms of account receivables and inventories. However, the same advantages are not shown in account payables conversely. It is inferred that SEC supports Samsung Group through giving looser credits. To sum up, as far as cash flows are concerned, SEC is capable of operating with sufficient working capital because of diversification and cross-investment within the Group. Meanwhile, SEC exhibits superior financial ratios than its peer companies as Group's cooperation. Subsequently, it is concluded that SEC gains much stronger competitive advantages from Samsung Group.